Applications of metadynamics to drug design-related issues Andrea Cavalli 1Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy The methadynamics method1 is a relatively new molecular dynamics technique aimed at both enhancing the sampling of regions separated in the phase space, and mapping out the free energy landscape as a function of a small number of parameters commonly referred to as collective variables. The metadynamics algorithm uses repulsive potentials that allow the system to escape from local minima over the lowest transition state, and discourage the system from revisiting the same points in the configurational space. In such a way, the method not only accelerates the simulation of rare events, but also maps out the free energy landscape as a function of chemically relevant collective variables. This lecture reports on applications of metadynamics to drug design-related issues. To illustrate the potential of metadynamics as docking tool, the dynamics of the tetramethylamonium (TMA) penetration of human acetylcholinesterase gorge will be discussed.2 Then, applications of metadynamics to docking experiments will be presented. In particular, we will show the use of metadynamics as a post-docking tool to discriminate among different minima identified by means of conventional docking software (GOLD, AutoDock, etc.) and cluster analysis performed with the algorithm AClAP.3 Applications of metadynamics as a post-docking tool to the GSK3 and FabI enzyme-inhibitor complexes will be discussed. [1] Laio A, Parrinello M. Escaping free-energy minima. Proc. Natl. Acad. Sci. USA 2002, 99, 12562-12566. [2] Branduardi, D.; Gervasio, F.L.; Cavalli, A.; Recanatini, M.; Parrinello, M. The role of the peripheral anionic site and cation-π interactions in the ligand penetration of the human AChE gorge. J. Am. Chem. Soc. 2005, 127, 9147-9155. [3] Bottegoni, G.; Rocchia, W.; Recanatini, M.; Cavalli, A. AClAP, Autonomous hierarchical agglomerative Cluster Analysis based Protocol to partition conformational datasets. Bioinformatics 2006, 22, e58-e65.
Applications of metadynamics to drug design-related issues / Cavalli A.. - STAMPA. - (2007), pp. ---. (Intervento presentato al convegno Sixth European Workshop in Drug Design tenutosi a Siena nel 3-9 Giugno 2007).
Applications of metadynamics to drug design-related issues
CAVALLI, ANDREA
2007
Abstract
Applications of metadynamics to drug design-related issues Andrea Cavalli 1Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy The methadynamics method1 is a relatively new molecular dynamics technique aimed at both enhancing the sampling of regions separated in the phase space, and mapping out the free energy landscape as a function of a small number of parameters commonly referred to as collective variables. The metadynamics algorithm uses repulsive potentials that allow the system to escape from local minima over the lowest transition state, and discourage the system from revisiting the same points in the configurational space. In such a way, the method not only accelerates the simulation of rare events, but also maps out the free energy landscape as a function of chemically relevant collective variables. This lecture reports on applications of metadynamics to drug design-related issues. To illustrate the potential of metadynamics as docking tool, the dynamics of the tetramethylamonium (TMA) penetration of human acetylcholinesterase gorge will be discussed.2 Then, applications of metadynamics to docking experiments will be presented. In particular, we will show the use of metadynamics as a post-docking tool to discriminate among different minima identified by means of conventional docking software (GOLD, AutoDock, etc.) and cluster analysis performed with the algorithm AClAP.3 Applications of metadynamics as a post-docking tool to the GSK3 and FabI enzyme-inhibitor complexes will be discussed. [1] Laio A, Parrinello M. Escaping free-energy minima. Proc. Natl. Acad. Sci. USA 2002, 99, 12562-12566. [2] Branduardi, D.; Gervasio, F.L.; Cavalli, A.; Recanatini, M.; Parrinello, M. The role of the peripheral anionic site and cation-π interactions in the ligand penetration of the human AChE gorge. J. Am. Chem. Soc. 2005, 127, 9147-9155. [3] Bottegoni, G.; Rocchia, W.; Recanatini, M.; Cavalli, A. AClAP, Autonomous hierarchical agglomerative Cluster Analysis based Protocol to partition conformational datasets. Bioinformatics 2006, 22, e58-e65.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
